Arsenic poses unique problems for environmental health scientists in that it is recognized as a human carcinogenic but is not carcinogenic in animal models. Furthermore, arsenical compounds do not induce gene mutations, although they do potentiate the genotoxic effects of other mutagens and are associated with chromosomal abnormalities. These properties indicate that arsenic has a mode of action different from other well-characterized environmental carcinogens whose actions are mediated by DNA damage. One hypothesis is that arsenic acts through epigenetic mechanisms; arsenic may produce reversible cell alterations that influence the expression of genes involved in growth and differentiation. The purpose of this proposal is to investigate the effects of arsenic exposure in the context of an ongoing population based case control study of bladder cancer. We hypothesize that DNA methylation of genes in the causal pathway for disease will occur with a higher frequency in cases with bladder cancer who are also exposed to high levels of arsenicals. Thus, we propose to investigate methylation and mutation of genes in the causal pathway for the genesis of bladder cancer, with special attention to their association with exposure to arsenic.